Researchers at the University Medical Center Göttingen (UMG) and the Göttingen Cluster of Excellence “Multiscale Bioimaging” (MBExC) have shown how a minimal change in a single ion channel increases the sensitivity of sensory cells in the inner ear. Even soft sounds, such as a whisper, are perceived more clearly, but can cause prolonged overloading, which may ultimately lead to long-term hearing loss.
These findings deepen our understanding of how sound information is encoded in the ear. The results have been published in the journal Science Advances.
Uncovering the Role of CaV1.3 in the Inner Ear
Hearing begins in the inner ear, where specialized sensory hair cells convert mechanical sound waves into electrical signals that travel to the brain. This process relies on calcium channels—specifically the CaV1.3 subtype—to open in response to voltage changes and allow calcium ions to enter the cell. That influx triggers the release of neurotransmitters to auditory nerve fibers, passing the signal along the auditory pathway.
Senior author Prof. Dr. Tobias Moser, director of the Institute of Auditory Neuroscience at the University Medical Center Göttingen (UMG) as well as speaker of the Göttingen Cluster of Excellence „Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells“ (MBExC), and first author Dr. Nare Karagulyan, Postdoctoral researcher at the Institute of Auditory Neuroscience at UMG as well as member of the Hertha Sponer College at the Göttingen Cluster of Excellence MBExC. Credit: UMG/Swen Pförtner
The study, led by Prof. Dr. Tobias Moser, Director of the Institute for Auditory Neuroscience at UMG and Speaker of the MBExC, focused on a genetically modified variant of the CaV1.3 channel called CaVAG. This version is based on a minute change in the genetic blueprint of the CACNA1D gene. Yet this small mutation dramatically alters how the channel responds to sound: it opens more easily, requiring lower voltage to activate and transmitting signals even at very low sound levels.
“The CaVAG calcium channel has a lower activation threshold and opens in response to the same stimulus much sooner than an intact channel,” the researchers note. “The CaVAG variant of the CaV1.3 channel has also been described in humans and has been linked to an increased risk of autism spectrum disorders in children.”
Using an animal model, the team demonstrated that this increased sensitivity doesn’t just enhance hearing—it overstimulates the auditory system. “While the increased sensitivity of the altered CaV1.3 channel may help to better perceive soft sounds more clearly in the short term, our animal model showed that some synapses between sensory hair cells and auditory nerve cells ultimately lose their structure over time – without any exposure to loud music or other noise,” said Prof. Moser.
“The ‘normal’ background noise in the animal house alone is apparently sufficient for this. It looks as if the overactive calcium influx caused by the mutation overloads the system.”
A Potential Mechanism for Hidden Hearing Loss
One of the most intriguing aspects of the research is its potential link to hidden hearing loss—a form of auditory dysfunction not detected by standard hearing tests. Individuals with hidden hearing loss often report difficulty understanding speech in noisy environments despite having “normal” audiograms.
Calcium channels of synapses of sensory hair cells couple the sound stimulus to the excitation of the auditory nerve. Compared to the intact CaV1.3 channel (wild type, left), the genetically modified CaVAG variant, which is based on a minimal change in the blueprint of the CACNAD1 gene, causes activation of the synapses of sensory hair cells in response to very weak sound stimuli and thus leads to increased auditory nerve activity. The mouse model shows that the increased voltage sensitivity of the channel results in damage to the synapses due to overexcitation even at everyday sound levels. Image Credit: Nare Karagulyan/Tobias Moser
The researchers found that the heightened voltage sensitivity of the CaVAG channel not only reduced the response threshold of auditory nerve fibers but also increased their spontaneous firing—even in silence. Over time, this hyperactivity led to degradation of the synaptic structures between hair cells and nerves, pointing to a form of long-term damage driven by chronic overstimulation rather than external noise trauma.
“These findings deepen our understanding of how sound information is encoded in the ear,” said Dr. Nare Karagulyan, first author of the study and a postdoctoral researcher at UMG and the MBExC Hertha Sponer College. “They also highlight the fine balance between sensitivity and vulnerability in the auditory system.”
The findings also raise caution for individuals who may carry the CaVAG mutation.
“The new findings suggest that such individuals may be particularly sensitive to sound and at the same time highly susceptible to noise-induced damage”
“The study therefore recommends monitoring affected individuals audiologically over the long term and suggests considering preventive hearing protection in everyday noise exposure.”
Implications for Audiology and Clinical Care
Although the CaVAG variant has been associated with neurodevelopmental conditions such as autism, its implications for auditory health are just beginning to come into focus. In collaboration with teams from the Shanghai Institute of Precision Medicine and the University of Innsbruck, the Göttingen researchers established a clear causal relationship between the altered calcium channel function and downstream changes in nerve activity and structure.
For audiologists and hearing healthcare professionals, the study offers a compelling molecular explanation for hearing complaints that go unmeasured in standard clinical settings. It also reinforces the need for a more nuanced approach to hearing assessment—one that considers the possibility of synaptic or neural fatigue even in patients with otherwise normal thresholds.
While genetic testing for such variants is not yet routine in hearing healthcare, this research underscores its potential relevance in complex or unexplained cases of hearing difficulty, particularly those with early onset or rapid progression.
Reference:
Nare Karagulyan et al. ,Gating of hair cell Ca2+ channels governs the activity of cochlear neurons. Sci. Adv.11,eadu7898(2025). DOI:10.1126/sciadv.adu7898
About the Göttingen Cluster of Excellence MBExC
The Göttingen Cluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells” (MBExC) has been funded since January 2019 as part of the Excellence Strategy of the German federal and state governments. With a unique research approach, MBExC investigates the disease-relevant functional units of electrically active heart and nerve cells, from the molecular to the organ level, using innovative imaging techniques such as optical nanoscopy, X-ray imaging and electron tomography. To this end, MBExC brings together numerous university and non-university Göttingen Campus partners. The overarching goal: to understand the connection between heart and brain diseases, to carry out basic and clinical research and to develop new methods.
